The AWARE Study (Analysis of Safety Outcomes with Anti-VEGF Treatment) is expected to expand retinal specialists' knowledge of the short- and long-term risks of anti-vascular endothelial growth factor treatments for neovascular age-related macular degeneration and diabetic retinopathy. The study may help identify a subset of patients susceptible to adverse events.
"The study team has been assembled; the search strategies into the database have been developed, tested, and refined using the incomplete Medicare database. The study was approved, and the complete Medicare database is currently being loaded," said Scott W. Cousins, MD, lead ophthalmologist of the AWARE Study and director of the Duke Center for Macular Diseases and the Robert Machemer, MD, Professor of Ophthalmology at the Duke University Eye Center, Durham, NC.
The first pass of the formal data analysis is slated to begin soon, according to Dr. Cousins. The study is a longitudinal study that will continue potentially into the future, he noted.
"We will be conducting repeat analyses as the database is continually updated, providing opportunities for increasingly robust results," Dr. Cousins said.
Basis of the study
Frequently used treatments for neovascular AMD include verteporfin (Visudyne, Novartis), pegaptanib (Macugen, OSI/Eyetech/Pfizer), and ranibizumab (Lucentis, Genentech)-all of which are FDA-approved for this indication-and triamcinolone acetonide (Kenalog, Bristol-Myers Squibb) and bevacizumab (Avastin, Genentech), which are used off-label.
Analyses of the major anti-VEGF trials have indicated that these drugs are associated with potentially serious adverse events, namely, cerebrovascular events, cardiovascular events, gastrointestinal perforation, systemic hypertension, bleeding, and renal dysfunction.
Pegaptanib, for example, was found to be associated with cardiovascular deaths (1%), non-fatal myocardial infarctions (0.7%), and non-fatal strokes (0.7%) in the VISION Trial. Rates of serious vascular deaths and non-fatal myocardial infarctions were reported in the ANCHOR Trial to be 4.2% with use of ranibizumab 0.5 mg, 2.1% with use of ranibizumab 0.3 mg, and 2.1% with use of photodynamic therapy. Safety data in the MARINA trial indicated that both doses of ranibizumab (0.3 and 0.5 mg) resulted in 4.6% and 4.2% rates of adverse events, respectively. Interim results of the SAILOR trial indicated that ranibizumab 0.5 mg was associated with a higher incidence of strokes compared with the 0.3-mg dose (1.2% versus 0.3%, respectively).
Identifying this association is important in these patients because they are older and already at increased risk of developing cardiovascular disease and stroke. A better understanding of the risk-benefit ratio associated with anti-VEGF drugs is essential for appropriate patient management.
Dr. Cousins said that the study serves an unmet need in that the current postmarketing safety surveillance is not effective. The study will provide scientific leadership with the opportunity to develop new approaches to safety surveillance. And an underutilized resource, the large Medicare database of claims, can be tapped to help answer important questions about safety.
Results of the pivotal drug trials have demonstrated that no statistically significant increase in systemic adverse events exists. Other factors, however, must be considered, according to Dr. Cousins.
"All these drugs get into blood at pharmacological levels," he said. "In addition, the trials were not powered for small but clinically relevant rates. No safety data are available for off-label use of bevacizumab. [And] patients treated in the real world are likely to be less healthy compared with the patients enrolled in the pivotal trials."
In the AWARE Study, "we are testing the hypothesis that there might be increased cardiovascular complications in patients receiving intraocular anti-VEGF therapy compared with those not being treated with these drugs," Dr. Cousins said. "We are exploring whether there are differences among the various anti-VEGF treatments."